42 Medical interventions for diabetic retinopathy

Background

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes mellitus. Overall, diabetic retinopathy is estimated to be the most frequent cause of new blindness among adults aged 20–74 years, especially in the young-onset, type 1 group.1 The risk of retinopathy is directly related to the degree and duration of hyperglycaemia.2

Definition/classification

Patients whose eyes have microaneurysms only, with or without associated retinal oedema, are classified as having mild, non-proliferative diabetic retinopathy. A patient is classified as having moderate or severe non-proliferative diabetic retinopathy, depending mostly on the extent and severity of intraretinal microvascular abnormalities, intraretinal haemorrhage and venous beading.3

Proliferative diabetic retinopathy is defined as the presence of new vessels on the surface of the retina or optic disc. Patients with neovascularisation of the disc progress more rapidly and therefore have a worse prognosis.3–5

Prevalence/incidence

In the Wisconsin Epidemiologic Study of Diabetic

Retinopathy (WESDR) the frequency of any visual impairment in people with diabetes was 7·8%.6 In the clinicbased Insulin-Dependent Diabetes Mellitus Patients in Europe (EURODIAB IDDM) Complications Study, 2·3% of patients aged 15 to 50 years were blind. In a sample of African Americans with type 1 diabetes obtained from hospital admissions in New Jersey, 11% were visually impaired and 3·1% of patients were legally blind.7–9

The prevalence of blindness due to diabetic retinopathy was similar for African Americans (5%) and Caucasians (6%) with type 2 diabetes in the population-based Baltimore Eye

Study, although the rate of visual impairment was higher in African Americans.10

In the WESDR, the estimated annual incidence rate of blindness due to diabetes was 3·3 per 100 000 population. In all groups, the frequency of macular oedema increased with increasing duration of diabetes.11

Aetiology/predictors/risk factors

Loss of vision due to retinopathy is more likely to be associated with proliferative retinopathy in type 1 diabetes and with macular oedema in type 2 diabetes.

In the main randomised controlled trial, the United Kingdom Prospective Diabetes Study (UKPDS), risk factors were assessed after three months’ diet from the time of diagnosis of diabetes.12 By six years 22% of 1919 patients with no retinopathy had developed retinopathy – that is, microaneurysms in both eyes or worse.

Development of retinopathy (incidence) was strongly associated with baseline glycaemia, glycaemic exposure over six years, higher blood pressure and with not smoking.

Microaneurysms are important predictive lesions for progression of diabetic retinopathy. Six years after diagnosis, 5·6% of type 2 diabetes patients with five or more microaneurysms had photocoagulation or vitreous haemorrhage.13–15

Data from epidemiologic studies suggest the following important predictors of progression of retinopathy.

●Metabolic control: elevated glycated haemoglobin and the glycaemic exposure over time are strongly related to the incidence and progression of diabetic retinopathy in people with type 1 and type 2 diabetes.16–18

●Ethnicity: data from several studies are conflicting but a nationwide US population-based study revealed greater prevalences of diabetic retinopathy in non-Hispanic African Americans (27%) and Mexican Americans (33%) than in non-Hispanic Caucasians (18%).19

●Duration of diabetes and age: diabetic retinopathy is rare before the age of 10 years, regardless of the duration of diabetes. Vision-threatening retinopathy is not observed under age 15 and affects 2·5% of people aged 15–19.20

●Elevated blood pressure: elevated blood pressure is an independent risk factor for any retinopathy, macular oedema and loss of vision in both type 1 and type 2 diabetes.21–24

●Lipids: lipid deposits, especially when they are beneath the centre of the macula, are associated with retinal damage and permanent loss of vision.25 The extent of these lipid deposits is correlated with serum lipid concentrations.26,27 In the Diabetes Control and Complications Trial (DCCT) and the Early Treatment Diabetic Retinopathy Research Study (ETDRS) elevated serum cholesterol was related to the development and severity of retinal hard exudates in the macula or the risk of visual loss (50% increase of relative risk (RR) when comparing serum cholesterol of less and more than 6·3 mmol/l at baseline).28,29 Interestingly, in the UKPDS there was no relationship between hard exudates, macular oedema and serum cholesterol (personal communication).

●Pregnancy: pregnancy is an independent risk factor for retinopathy progression with patients at greatest risk who have the poorest control at baseline, the largest improvement in glycaemic control during early pregnancy, hypertension and pre-eclampsia.30–32 Adverse outcomes in delivery are especially predicted by the severity of diabetic retinopathy in the first trimester.33

●Cigarette smoking/alcohol: neither cigarette smoking nor alcohol consumption appear to be independent risk factors for retinopathy.34,35 The UKPDS established an association of reduced incidence of retinopathy with current smoker status (odds ratio (OR) for retinopathy 0·63, 95% CI 0·48–0·82).36

Prognosis

The baseline severity of retinopathy strongly predicts the prognosis. Untreated eyes with high-risk proliferative retinopathy are at very high risk of blindness.37,38

The natural history of the development of sightthreatening retinopathy is approximately constant from discovery of any retinopathy36: one third of those with retinopathy of more than microaneurysms progress to photocoagulation by 12 years.

Question

What is the effect of diabetes control in preventing/treating diabetic retinopathy?

The evidence

In the DCCT, 1441 patients with type 1 diabetes (726 with no retinopathy, 715 with mild-to-moderate nonproliferative retinopathy at baseline) were randomly assigned to receive either intensive or conventional insulin

therapy. The mean follow up was 6·5 years. There was a reduction in the rate of the development or progression of retinopathy, diabetic nephropathy and neuropathy among patients assigned to intensive treatment.39 For development of serious retinopathy the number needed to treat (NNT) 5 years was 4 (95% CI 2–20).

In the UKPDS, of 3867 newly diagnosed type 2 diabetes patients, 2729 patient were randomly assigned to intensive treatment aiming for fasting plasma glucose levels less than 6 mmol/l and 1138 patients were allocated to conventional dietary treatment aiming at fasting plasma glucose levels less than 15 mmol/l without hyperglycaemic symptoms. Most of the relative risk reduction in the main outcome “any

diabetes-related aggregate end-point” (NNT10years 20, 95% CI 10–500) was due to a 25% relative risk reduction (RR

7–40, P = 0·0099) in microvascular end-points, including the need for retinal photocoagulation.

Comment

Improved glycaemic control is associated with fewer microvascular end-points. This is in concordance with observational studies, implicating hyperglycaemia in the development of chronic microvascular complications of diabetes.

Question

Is there an association between rapid improvement of glycaemic control and progression of diabetic retinopathy?

The evidence

When intensive treatment is to be instituted in patients who have proliferative or severe non-proliferative retinopathy, ophthalmological consultation is desirable because photocoagulation may be indicated. Better control of hyperglycaemia lowers but does not eliminate the risk of retinopathy and other complications of diabetes. The DCCT39 and other investigators40 have shown that early deterioration of retinopathy at the time of normoglycaemic re-entry is possible. This deterioration was most marked in those with more advanced retinopathy.29,41

Comment

It appears that patients with proliferative retinopathy should be treated simultaneously with photocoagulation and intensified insulin therapy and have to be followed up carefully.42

Question

What are the effects of blood pressure control on diabetic retinopathy?

The evidence

In the UKPDS, all patients had their blood pressure checked at three-monthly intervals, and 22% were part of the blood pressure control study, two thirds of whom had tight control of their blood pressure.24 A total of 1148 patients with type 2 diabetes and hypertension were stratified for presence or absence of previous hypertensive treatment, while 758 patients were allocated to tight blood pressure control aiming for a blood pressure of less than 150/85 mmHg by first-line use of captopril or atenolol. Tight blood pressure control reduced the risk for diabetesrelated complications or death, stroke and microvascular

disease. The NNT10years for any complication was six (95% CI 3–10) and a 35% relative reduction of risk of retinal

photocoagulation was observed (P = 0·023).

Comment

Type 2 diabetes patients with hypertension and tight blood pressure control have a reduced risk of developing a diabetesrelated clinical end-point, diabetes-related death, stroke and microvascular disease. This treatment is also cost-effective.

Question

What is the effectiveness of screening or monitoring for diabetic retinopathy?

The evidence

A directive to reduce visual loss and blindness as a result of diabetes was embodied in the St Vincent Declaration of 1989.43 Diabetic retinopathy screening appears to offer a chance to reduce this major cause of blindness and partial sightedness in the working age group. A systematic review of the English language literature on screening and monitoring tests for diabetic retinopathy identified 22 prospective cohort studies comparing the screening method with a reference standard in a masked fashion.44 No randomised controlled trial could be identified and no formal meta-analysis was carried out.

Comment

The British Diabetic Association has proposed levels of at least 80% sensitivity and 95% specificity for screening tests

for diabetic retinopathy,45 which was used as the basis for assessing the effectiveness of the screening/monitoring tests in the systematic review. The authors concluded that retinal photography with mydriasis is the most effective strategy for screening. This is supported by an older systematic review/meta-analysis and other investigators.46–48

Direct ophthalmoscopy alone is inadequate with a sensitivity below 80% in most of the studies across all professional groups. Non-mydriatic polaroid prints achieved a poor detection rate of 56% even for sight-threatening diabetic retinopathy. The reviewers could not adequately address the question of the value of undertaking an examination of visual acuity in screening, who should perform the screening and where the screening should be carried out.

Question

Do all those with type 2 diabetes, who form by far the largest proportion of the diabetic population, need annual eye screening if treatable disease is not to be missed?

The evidence

A recent consensus document advised that diabetic patients should have annual screening for retinopathy.49 In the UKPDS cohort any patient with type 2 diabetes and little or no retinopathy was unlikely to progress to the need for photocoagulation for several years.36 If eyes were clear of retinopathy (or had only minimal lesions) the risk of progression to photocoagulation was slight (2/1000 patients in three years), provided blood pressure and glycaemia are under control. Such patients could be re-screened after three years.50,51 Moreover, on the basis of cost-effectiveness Vijan et al. suggested that screening should be tailored to the patients needs, rather than screening everybody annually.50,51

Comment

Retinal photography with mydriases is the preferred screening modality with less reliance on the status of the observer. There are conflicting data for screening intervals, which should probably be individualised, especially in highrisk patients.

Several systematic reviews/meta-analyses were performed on screening modalities indicating that retinal photography with mydriasis should form the basis of any formal screening programme. No study has clearly shown a decrease in blindness incidence directly attributable to a retinopathy screening programme. There are no adequate data to reach a definite conclusion either on screening intervals or the

effects of screening itself, both of which currently have to be estimated by reliance on competing models. Since critical factors for any screening programme’s effectiveness are prevalence of treatable disease among screened patients, test validity and treatment effectiveness, efficiency may be increased by tailoring screening to the patients’ needs and risk profile.

Question

What are the effects of pharmacological interventions for diabetic retinopathy?

The evidence

No systematic review on the effects of pharmacological treatments for diabetic retinopathy could be found. A number of randomised controlled trials investigating various drugs were found. At present, there is no firm evidence for the value of any drug, mainly because the studies have been too small, of poor quality and the assessments have often been subjective and not independent from the observers. These trials are summarised in Tables 42.1 and 42.2. Only the calcium dobesilate, aldose reductase inhibitors (ARIs) and lisinopril trials had more than 100 participants.

Pharmacological interventions

Aldose reductase inhibitors (sorbinil, tolrestat and ponalrestat)

In seven randomised controlled trials (six of double-blind design) 56 patients were treated with aldolase reductase inhibitors (ARIs). Aldose reductase facilitates the conversion of glucose to sorbitol, which accumulates in cells during hyperglycaemia and may result in cell death.52–58 Only one study provided a power calculation. One trial with a topical ARI reported significant differences in reversion of reduced corneal sensitivity and abnormal morphological characteristics of corneal epithelial cells.

Angiotensin converting enzyme inhibitors (lisinopril)

A randomised double-blind trial of lisinopril suggested that inhibition of this enzyme or blood pressure lowering, even in non-hypertensive patients, may slow the progression of diabetic retinopathy.59 The primary endpoint was the urinary albumin excretion rate. The authors also provided a power calculation for the secondary endpoint – retinopathy (80% power to detect a reduction in

retinopathy progression from 24% on placebo to 10% on lisinopril).

The HbA1c adjusted odds ratio for progression to proliferative retinopathy was 0·20 (95% CI 0·04–0·91) in

favour of lisinopril versus placebo (calculated NNT2years = 19). The Diabetic Retinopathy Candesartan Trials (DIRECT) large

scale study is now in progress to confirm these findings. DIRECT consists of three randomised, double-masked, parallel, placebo controlled to determine the impact of treatment with candesartan on diabetic retinopathy. It is anticipated that it will be completed in 2004.

Data from the UKPDS suggest that the blood pressure lowering rather than a specific retinal vascular response to the inhibition of angiotensin-converting enzyme may be responsible for slowing the progression of retinopathy, as both captopril and atenolol (a beta-adrenergic antagonist) slowed the progression of retinopathy equally well.60,61

Antioxidants

In one controlled clinical trial the effects of buckwheat herbs, ruscus extract and troxerutin were compared with each other.62 The study had no power calculation and did not supply relevant statistics. Vitamin E was given to 36 patients in one randomised double-blind trial and resulted in improved retinal haemodynamics.63 The study provided a power calculation.

Antiplatelet agents

A systematic review of randomised controlled trials of aspirin therapy in people with diabetic retinopathy concluded that the treatment with aspirin did not affect the progression of retinopathy, the risk of visual loss or the risk of vitreous haemorrhage among patients with proliferative retinopathy.64 It concluded that there are no ocular contraindications to taking aspirin if required as part of a treatment for cardiovascular diseases65 or other medical indications.

Ticlopidine was investigated in two randomised doubleblind studies administering 500 mg ticlopidine per day for three years to 269 patients.66,67 The larger trial67 reported a significant decrease in the number of definite microaneurysms, weighted for angiographic quality (0·48 ± 5·79 microaneurysms per year in the ticlopidine versus 1·44 ± 4·67 in the placebo group, P = 0·03). Thirteen per cent of patients receiving ticlopidine had to discontinue treatment due to adverse effects. Neither study provided a power calculation.

Calcium dobesilate

In eight randomised or controlled clinical trials (seven of double-blind design) around 280 patients received calcium

dobesilate (an “angioprotective” agent, thought to reduce microvascular hyperpermeability)68–74 No study provided a power calculation. Two studies reported “significant” differences, for example, in microaneurysms, haemorrhages or capillary hyperpermeability, but did not supply the relevant statistics.

Clofibrate

One randomised double-blind trial in 15 patients investigated clofibrate (a blood lipid reducing

agent).75 The study did not provide a power calculation.

Cyclandelate

Two randomised double-blind trials investigated the effects of cyclandelate (a compound thought to have stabilising effects on the blood–retinal barrier; its metabolites could also have ARI-inhibiting activities) in 25 patients.76,77 Neither study reported a power calculation.

Danaparoid sodium

Two trials investigated the effects of danaparoid sodium (a mixture of glycosaminoglycans consisting mainly of heparan sulfate, thought to induce a regression of retinal hard exudates) in 21 patients.78,79 Both studies had a randomised double-blind design, and one early report provided a retrospective analysis of the trial. One study supplied a power calculation.

Factor VIII

Bovine factor VIII derivative (thought to have positive effects on capillary basement membranes and on vascular endothelium) was given to 15 patients in one randomised double-blind trial.80 The study had no power calculation.

Gingko biloba

In one randomised double-blind trial 14 patients were treated with gingko biloba (a medicine thought to protect cell membranes in retinopathy and have oedema-reducing efficacy).81 The study had no power calculation. Due to multiple comparisons in a small group of patients the partly significant study results have to be interpreted with caution.

Methandienone

In one randomised single-blind study 44 patients received methandienone (an anabolic steroid that can be given by mouth).82 The study had no power calculation.

Naftidrofuryl

In one randomised double-blind trial 23 patients were treated with naftidrofuryl (a compound thought to reduce platelet aggregation as well as influence plasticity of erythrocytes).83 The authors reported a low post hoc power estimation of 50%.

Pentoxifylline

One randomised double-blind trial in five patients investigated pentoxifylline (a methylxanthine thought to improve blood flow velocity and blood viscosity).84 No power calculation was reported. Some significant differences for retinal capillary blood velocity were shown.

Somatostatin analogues

In two randomised controlled pilot trials the use of octreotide (a growth hormone inhibiting somatostatin

analogue with antiproliferative effects) was explored in 21 patients.85,86 No study reported a power calculation. Large-scale studies on the efficacy of somatostatin analogues are in progress.

Sulindac

One randomised double-blind trial examined the use of sulindac in 12 patients.87 No power calculation was performed.

Comment

At the moment, pharmacological therapy of diabetic retinopathy does not appear to be useful with regard to relevant end-points, such as progression of retinopathy. Better therapeutic principles have to be discovered (for example, trials investigating inhibition of protein kinase Cβ 288 are in progress) and well assessed in adequately powered trials.

Summary

Thirty-six studies investigated 20 different compounds thought to influence the course of diabetic retinopathy. Approximately half of the trials was performed with calcium dobesilate or aldose reductase inhibitors. With the exception of antiplatelet agents around 1100 patients were investigated for a maximum of two and a half years showing no significant effects of pharmacotherapy for diabetic retinopathy.

Implications for practice

Improved glycaemic control is associated with fewer microvascular end-points. Tight blood pressure control in type 2 diabetes patients reduces several diabetes-related end-points as well as microvascular disease. There are no ocular contraindications to aspirin if required for medical indications. At the moment, any other pharmacological therapy of diabetic retinopathy does not appear useful with regard to relevant clinical end-points.

Implications for research

Randomised controlled, high-quality long-term trials of adequate power investigating new therapeutic principles should focus on patient-oriented outcomes, such as prevention or progression of retinopathy, and health-related quality of life and costs.

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